beta-alkyl-substituted ethylamines



Patented Oct. 31, 1944 B ALKYL- SUBSTITUTED ETHYLAMINES Hans-Georg Allardt, Phillppsthal, Kra. Teltow,

and Karl Junkmann, Berlin, Germany, assignors to Schering Corporation, Bloomfield, N. 1., a corporation of New Jersey No Drawing. Application February 25, 1938, Se.- 11:31 I No. 192,642. In Germany February 20.

3 Claims. ('01. 200-583) individual amines standardisation is effected by This invention relates to a process for the manufacture of p-alkyl-substituted ethylamine derivatives and to the products obtained thereby.

'The invention is based on our discovery that p-a'llryl-substituted ethyiamine derivatives of the following formula:

in which R, R and R" indicate the same or different allLvl residues, or Rfiand/orR" can also or their water-addition products, amides of the formula:

RI! V are subjected to the action of reducing agents, for example of nascent or catalytically activated hydrogen'. It is also possible, however, to subject the amides of the corresponding acids, which contain in the molecule one carbon atom more than the amines to be produced, to the known degradation methods, for example those according to Hofmann or Curtius, or the like.

means of a still functioning rabbit intestine maintained permanently in Tyrodes solution containing barium. The individual preparations were always standardised against novocaine hydrochloride 'as comparison preparation, In these exp riments vnovocaine hydrochloride was equal to 1/75 papaverine hydrochloride. From the following table it is seen that p-alkyl-substituted ethyamin'es, the number of carbon atoms of which is low, possess only a moderate peripheral paralytic effect. The activity rises however in an astonishing mannenquite considerably when the molecule of the substances contains at least 11 carbon at ms and, in fact, such an increase takes place that the amines become equal in effect to papaverine or even excel it. Thefactivity,--however, fails when the carbon atom content rises above 18.

Activity No. Ethylamine examined G-No. novocainhyloride l) Bfifi-Triethyl-ethyiamlne hydrochloride. 8 7. 5

Trl ro lethylamine hydrochloride. ll n-tet ra e hydrochloride 14 76 Dieth l n hexylethylamine hyi2 rochlo de. MDi-n-hexylethylamine hydrochloride. 14 pggr-Etiligadi-n-butylethylamine hy- 12 an 00 e. pflph-lEtgyldiisoamylethylamine hydro- 14 110 c or e. Bfig-d'lri-n-butylethylamine hydrochloi4 450 e. fiflqlri-isoamylethylamine hydrochio- 17 300 r e. I

flfiflllrbn-hexylethylamlne hydrochlo- 20 r e. I

ture of the hitherto unknown p-ethylamine de-' rivatives a new group of therapeutically important substances with strong spasmolytic properll'or the technical manufacture it has proved to be most advantageous to reduce the said nitriles or amides in the presence of non-noble metal catalysts suitably precipitated on carriers, preferably nickel catalysts precipitated on kieselguhr, with hydrogen under super-atmospheric reduction can also be carried out at lower temperature, for example at 70 C.

To establish the spasmolytic activity of the ties has been discovered.

The following examples illustrate the invention, the parts being by weight:

Example. 1

the catalyst the contents of the autoclave are fractionally distilled.

The distillation yields about 95% of the theoretical quantity of pure fl-tri-n-butylethylamine of B. P. 140-142" C. under 13 mm.

By neutralisation of the base with the calculated quantity of hydrochloric acid and evaporatlon, there is obtained therefrom the hydrochloride in the form of leaflets of M. P. 135-136 C, (from water) Example 2 200 parts of tri-n-butylacetamide (M. P. 61-62 C.; B. P. l83-l86 C. under 12 mm.) are heated under hydrogen pressure to 120-150 C. in an autoclave with the addition of 25 parts of nickel catalyst obtained from precipitated basic nickel carbonate which has been reduced 1 hour at 450 C. The water produced in the reaction is blown 60 parts of ethyl-di-isoamylacetonitrile (B. P. 129-132 C. under 12 mm.) (obtained according to German Patent No. 570,594 from butyronitrile, sodamide, and isoamyl bromide) are dissolved in alcohol. Thereupon metallic sodium is gradually introduced into the boiling alcoholic solution. After distilling off with steam, the amine, obtained by the customary methods from theflsteam distillate, is subjected to fractional distillation. The e-ethyl-,8-diisoamylethyla.mine has the B. P. 12'6-128 C. under 12 mm. Its hydrochloride crystallises from dilute hydrochloric acid and has the M. P. 94-96" C. It is easily soluble in benzine and slightly soluble in water. The amine is obtained in better yields than by the above described process, when ethyl-di-isoamyl-acetonitrile is reduced according to the process of Example 1 or when the ethyl-di-isoamyl-acetamide of B. 1?. 178 C. under 12 mm. and M. P. 50 C., easily obtainable from the nitrile by adding on water by means of sulphuric acid at 150, is subjected to reduction according to Example 2.

In a corresponding manner other high molecular amines can also be obtained.

Example 4 di-n-hexylacetonitrile 76 parts of (B. P.

164-167 C. under 22 mm.) are treated in a shaking vessel with the addition of 3 parts of Raney catalyst at 70 C. under a pressure of about 30 cms. of water with pure hydrogen so long as hydrogen is taken up (about 16.5 litres in all). The reaction product is then separated from catalyst and fractionally distilled. The p-di-n-hexylethylamine obtained exhibits the B. P. 146-148 C. under 15 mm. Its picrate melts at 162 C. (leaflets from methanol). The hydrochloride has the M. P. 124-125 C., it dissolves easily in petrol ether, ether, benzene, carbon tetrachloride and slightly in cold water; the hot aqueous solutions set on cooling to a jelly.

The di-n-hexylacetonitrile serving as starting material is produced in known manner by converting cyanacetic acid ethyl ester by reaction with sodium alcoholate and hexyl bromide into di-n-hexylcyanacetic acid methyl ester of B. P. 17-4-178 C. under 10.5 mm. By saponiflcation with alcoholic caustic soda lye at room temperature there is obtained therefrom the sodium salt of the di-n-hexylcyanacetic acid. The free acid splits oil carbon dioxide at 350 C. and gives in over yield the di-n-hexylacetonitrile.

Where in the claims we speak of the p-alkylsubstituted ethyl amines, their salts, such as the hydrochlorides, are to be understood as equivalents.

Having now particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is: I

1. A spasmolytic agent for producing peripheral paralysis in the animal organism, comprising fi-tri-n-butylethylamine compound of the general formula CuHsiN and the structural formula omonicnicm CH:CH:CH3CHr-C-CH:NH

cn cnlomcm having a B. P. -142" C. under 13 mm.

2. A spasmclytic preparation for producing peripheral paralysis in the animal organism, comprising p-tri-isoamyl ethyl amine.

3. A spasmolytic agent for producing peripheral paralysis in the animal organism, comprising a p-alkyl-substituted ethylamine derivative of the following general formula R-C.CH:.NH;

wherein R, R, and R" represent the same alkyl residue, said derivative having at least 11 and, at the most, 18 carbon atoms.

KARL JUNKMANN. HANS-GEORG ALLARUI. 

